Pancreatic adenocarcinoma (PDAC) is a remarkably aggressive malignancy associated with high rates of metastasis and poor therapy response. It is currently the 4th leading cause of cancer related deaths in developed countries and despite efforts to improve treatment options, the median overall survival remains <1 year. Therefore it is important to identify new targets that promote disease aggressiveness and therapy resistance. Our lab and others have previously identified the RNA-binding protein Musashi (Msi) as critical for the development of multiple malignancies. We have demonstrated that Msi2 is aberrantly upregulated during disease progression in chronic myeloid leukemia and inhibition of Msi2 results in a significant increase in overall survival in de novo mouse models of leukemia. However, it was unclear if Msi2 is important in the progression of solid tumors. In this regard, we tested for Msi2 expression in patient pancreatic cancer samples and determined that indeed protein expression increases during the onset and development of PDAC. By utilizing a genetic mouse model of pancreatic cancer crossed to Msi2-/- mice, we found that Msi2 blockade significantly slows tumor development and results in increased overall survival. Moreover, we determined that Msi2+ pancreatic cancer cells are enriched for tumor-propagating ability. These data suggest that Msi2 functionally contributes to PDAC progression. Therefore, we hypothesize that Msi2+ cells preferentially metastasize and survive chemotherapy. To test this we aim to (1) determine if Msi2+ tumor cells drive formation of metastasis and if Msi2 inhibition reduces metastatic burden, and (2) determine if Msi2+ cells are more resistant to chemotherapies and decipher the mechanisms by which they preferentially survive. The results of these studies have the potential to identify a key program in PDAC pathogenesis and define a subset of cells that specifically promote disease aggressiveness.